All of the genes known to be associated with increased susceptibility to breast cancer function within a common biochemical pathway involved in signaling the presence of and responding to DNA double-strand breaks. Upon exposure to ionizing radiation (IR), ATM phosphorylates a large number of downstream targets, including the protein products of BRCA1 and CHEK2, in which specific mutations have been shown to predispose to breast cancer. Signaling between ATM and Chek2 involves at least five other proteins, p53 binding protein (53BP1), and MDC1, Mre11, RadSO, and Nbs1 (the latter three forming the MRN complex). To delineate the roles of radiation exposure and genetic predisposition in the etiology of breast cancer, we propose a case-control association study to examine the interaction of IR exposure with genetic variation in these genes in a population-based sample of young women with bilateral and unilateral breast cancer. Our study hypothesis is that the incidence of contralateral breast cancer will be increased among women who carry mutant alleles, alone, or in combination with one another, and who received radiation therapy as part of their treatment for first primary breast cancer. To carry out the current proposal, we will use the 2100 cases and controls from our multi-center WECARE Study and access the already established comprehensive data and biorepository that includes, for all study participants, epidemiologic data, biological specimens, treatment records, radiation dosimetry, and ATM, BRCA1 and BRCA2 mutation carrier status. Our specific aims are: Aim #1. Identify haplotype block structures and tagging SNPs for CHEK2, TP53BP1, MDC1, MRE11, RAD50 and NBS1. Aim #2. Genotype all 2100 WECARE Study participants (700 triplets) using SNPs identified in Aim #1 and selected based on haplotype analysis of sequenced samples. Aim #3. Conduct a population-based case-control association study of 6 genes involved in the ATM-CHEK2 pathway to determine whether they are associated with an increased risk of radiation-induced contralateral breast cancer.